title: Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model.
abstract: Exposure to nonself red blood cell (RBC) antigens, either from transfusion or pregnancy, may result in alloimmunization and incompatible RBC clearance. First described as a pregnancy complication 80 years ago, hemolytic disease of the fetus and newborn (HDFN) is caused by alloimmunization to paternally derived RBC antigens. Despite the morbidity/mortality of HDFN, women at risk for RBC alloimmunization have few therapeutic options. Given that alloantibodies to antigens in the KEL family are among the most clinically significant, we developed a murine model with RBC-specific expression of the human KEL antigen to evaluate the impact of maternal/fetal KEL incompatibility. After exposure to fetal KEL RBCs during successive pregnancies with KEL-positive males, 21 of 21 wild-type female mice developed anti-KEL alloantibodies; intrauterine fetal anemia and/or demise occurred in a subset of KEL-positive pups born to wild type, but not agammaglobulinemic mothers. Similar to previous observations in humans, pregnancy-associated alloantibodies were detrimental in a transfusion setting, and transfusion-associated alloantibodies were detrimental in a pregnancy setting. This is the first pregnancy-associated HDFN model described to date, which will serve as a platform to develop targeted therapies to prevent and/or mitigate the dangers of RBC alloantibodies to fetuses and newborns.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Transfusion and Cellular Therapies, Children’s Healthcare of Atlanta, Division of Pediatric Hematology/Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Stowell
authors.forename: Kate L
authors.initials: KL
authors.lastname: Henry
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Smith
authors.forename: Krystalyn E
authors.initials: KE
authors.lastname: Hudson
authors.forename: Greg R
authors.initials: GR
authors.lastname: Halverson
authors.forename: Jaekeun C
authors.initials: JC
authors.lastname: Park
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Bennett
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Girard-Pierce
authors.forename: C Maridith
authors.initials: CM
authors.lastname: Arthur
authors.forename: Silvia T
authors.initials: ST
authors.lastname: Bunting
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Hendrickson
mesh_terms: D000743:Anemia, Hemolytic / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001803:Blood Transfusion; D016207:Cytokines / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D007626:Kell Blood-Group System / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011247:Pregnancy; D011270:Pregnancy, Animal
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D007518:Isoantibodies; D007626:Kell Blood-Group System; D049452:Green Fluorescent Proteins